In this application, the P.I. proposes to examine the role of ErbB4 signaling in the normal and neoplastic breast. Based on data from the ErbB4 transgenic mice showing the role of ErbB4 in lobuloalveolar development and the clinical data that ErbB4 expression is a positive prognostic factor in cancer, the P.I. hypothesizes that ErbB4 signaling plays a role in breast differentiation. To test this hypothesis, four specific aims are proposed: 1) to determine the normal function of ErbB4 in the developing mouse breast using Cre-lox recombination at both ErbB4 alleles to generate mammary-specific ErbB4 loss-of-function mutations; 2) to identify signaling networks of the oncogene HRGalpha in the mouse breast with a HRGalpha-null mouse; 3) to use a novel yeast "three" hybrid assay to identify ErbB4 regulated signaling proteins in the breast; and 4) to determine if ErbB4 signaling antagonizes ErbB2-induced breast cancer in a mouse model. These experiments are expected to identify ErbB4 signaling networks and determine their roles in both normal and neoplastic breast development.